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Objectives: tamsulosin hydrochloride is a new type ofα1A adrenergic receptor antagonist which was on sale in Japan for the first time in 1993. This product can significantly improve dysuria caused by benign prostatic hyperplasia and nighttime urinary frequency, residual urine sensation and other symptoms,it also can be super-selective blocking the bladder neck and prostate smooth muscle receptor and envelopeα1A receptors, reduce muscle tension, reduce lower urinary tract resistance, significant improvement in urinary symptoms, so as to achieve the purpose of treatment of benign prostatic hyperplasia,it has the minimal side-effects of similar drugs,and has little effect ofα-adrenergic receptor blocking on other parts,and it makes the site of action more clearly,so it,sα-blocker side effects is smaller.Methods: A method for preparation of tamsulosin hydrochloride push-pull osmotic pump release tablets was obtained by coating core tablet compressed by single punch tablet machine. Cellulose acetate, PEG 4000, acetone:wate(r100:3) were respectively used as coating material, channeling agent and solvent. On the basis of pretesting and scientific literatures, the temperature of coating, rotary speed of coating pot and pressure of spraying were determined. Single factor tests were carried out on the formulation of tablet core and coating material,procedure as well as the in vitro release condition,which affect the release behavivor were analyzed by similar factor method. The orthogonal experiment was designed to optimize formula in which the amount of PEO, the amout of NaCl,the amout of PEG 400, and thickness of coating membrane were taken as four influential factors and three different levels were selected to part, each of them was selected refer to the L9(34) orthogonal design table.According to accumulative release percentage at,4h,8h,12h to select optimal formula with the colligation evaluation. The osmotic pump tablet with the optimal formula was prepared and its in vitro cumulative release profile was obtained.In vitro release test was performed in a dissolution apparatus using the third method according to CHP. The stirring rates in 0.1mol/L HCl was 100rpm. The temperature was maintained at (37±0.5)℃. At the predetermined intervals (1, 2, 4, 6, 8, 10, 12h), 2ml samples were with drawn from each vessel, filtered with a 0.45μm membrane, and analyzed with HPLC method for tamsulosin hydrochloride. The same volume of fresh medium was replaced after sampling.Concentration of tamsulosin hydrochloride was determined using a HPLC system. Separation was achieved by using a Kromasil column(C18, 4.6mm×250mm,5μm).The mobile phase consisted of methanol–acetonitrile–Phosphate solution at a ratio of 30:20:50(v/v/v). The flow rate was 1.0ml/min, and the injection volume was 20μl. All chromatographic separations were performed at 25℃. The wavelength of detection was set at 223nm.The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, strong illumination and accelerated condition (60℃/75% RH for 6 months). At the end of the study period, the formula was observed for change in physical appearance, drug content and drug release characteristics.Pharmacokinetics study in vivo: we selected the Beagle dogs as laboratory animal, which were divided into two groups in random. One group was given push-pull osmotic pump release tablets and the other was given market sustained release tablets. Plasma samples were obtained at different times. Crossover experiment was taken after two weeks. HPLC with Fluorescence detector was adopted in examining concentration of plasma. Then pharmacokinetics parameters were caculated by non-compartmental model analysis method.Results: The optimal technology and formula were defined through simple factor test and orthogonal experiments. The core tablet conditions were as follows: hardness of tablet, 7～8kg; diameter of tablet, 7mm; weight of tablet, 140mg. The coating conditions were as follows: coating temperature, 40℃; rotation rate of pot, 35rpm; spray pressure, 2kg/cm2. The optimal formula were as follows: the type of osmotic agent, NaCl; osmotic agent in the drug of core tablet, 25%(g/g); PEG 4000 in the cellulose acetate, 10%(g/g); coating membrane in core tablet, 3%(g/g). Total coating materials in the coating solution: 3.0%(w/v).The results of the system serve experiment of the HPLC method to determine the content of tamsulosin hydrochloride: the reserve time of tamsulosin hydrochloride were about 4.5min, the recoveries were 98.96~100.12%, the within-day precision was 0.25~0.43%, the between-day precision was 1.04~1.85%. Regression equation was y=20858x-1961.3, (r=0.9993). The linearity range of tamsulosin hydrochloride was 1μg/ml~8μg/ml. Excipients had no interference with the results.Stability experiment: the result of high humidity test showed that 10 days after osmotic pump release tablets being placed in humidity(RH 92.5%), the weight highly increased. But in humidity(RH 75%), the weight hardly increased. There was no change in physical appearance, drug content and drug release characteristics after being stored at high humidity(RH 75%), high temperature(60℃) and strong illumination (4500±500 lx) for 10 days. The result of accelerated experiment showed that the data were not significantly different from before.Pharmacokinetic study: The main pharmacokinetics parameters were respectively as following: Tmax(h), Cmax(μg/ml) and MRT of osmotic pump tablet were 4.67±0.76, 3.33±0.92 and 17.09±2.284 respectively. Tmax(h), Cmax(μg/ml) and MRT of conventional capsule were 89.34±4.02, 5.86±1.79 and 1.84±1.28 respectively.Compared with tamsulosin hydrochloride, both peak time and MRT of osmotic pump tablet was extended and concentration of osmotic pump tablet was decreased.Conclusions: Tamsulosin hydrochloride push-pull osmotic pump tablets had good effect of controlled release property and repetition in vitro. The quality is independent on temperature, humidity and illumination. The methods of assay and dissolution for tamsulosin hydrochloride osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that both peak time and MRT of osmotic pump tablet was extended and plasma concentration of osmotic pump tablet was decreased.
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